It has been known that lowering a blood cholesterol level is effective in preventing atherosclerosis. In particular, the investigation conducted by U.S. Lipid Research Clinics Program has clarified that a decrease in blood cholesterol level correlates to the suppression of the incidence of cardiac coronary arterial diseases and that anion exchange resins are effective in preventing these diseases. Anion exchange resins which are publicly known to have been used as a cholesterol-lowering drug for lowering a blood cholesterol level, are for example cholestyramine which is a polymer of styrylmethyltrimethylammonium chloride, and a composition containing styrylmethyltrimethylammonium chloride (see U.S. Pat. Nos. 8,499,960 and 8,780,171 and Japanese Patent Laid-Open Gazette No. 10886/78). Further, a copolymer of imidazole with halomethyloxysilane, having a higher efficacy than cholestyramine, has been reported as another example (see Japanese Patent Laid-Open Gazette No. 124819/90). Furthermore, Japanese Patent Laid-Open Gazette No. 212505/90 disclose an acrylic polymer containing a quaternarized alkylammonium and a composition comprising the polymer as still other examples. However, the exchange capacity (from 1.98 to 3.66 meq Cl.sup.- /g) disclosed in this Gazette cannot be thought to be sufficiently large as compared with that of cholestyramine (2.9 meq Cl.sup.- /g; see U.S. Pat. No. 3,780,171). The compound disclosed in the Japanese Patent Laid-Open Gazette No. 212505/90 cited above involves a crosslinking unit as an essential constituent factor. Accordingly, this Gazette has neither disclosed nor suggested that non-crosslinked acrylic polymers disclosed in the present invention have an effect of lowering a cholesterol level.
It is believed that these anion exchange resins adsorb and fix bile acids thereto and thus promote the catabolism of cholesterol into bile acids to thereby lower a blood cholesterol level as will be discussed in greater detail hereinafter.
Bile acids are synthesized from cholesterol serving as a precursor thereof in the liver, secreted from the common bile duct into the intestinal tract, absorbed together with fat-soluble substances and then recovered into the liver, thus circulating through the bowels and the liver. Therefore, bile acids are present in a fixed amount in the cycle called the enterohepatic circulation without their systemic circulation (bile acid pool). When bile acids are bonded to an anion exchange resin in the intestinal tract and evacuated, the amount of bile acids pooled is reduced. As a result, cholesterol 7 .alpha.-hydroxylase is activated in hepatic cells and thus bile acids are biosynthesized. Then the cholesterol concentration in the liver is lowered. To make up for the decreased cholesterol concentration, LDL (low density lipoprotein) receptor appears on hepatic cell membranes and thus LDL cholesterol in the blood is recovered or withdrawn into the liver. As a result, the blood cholesterol level is lowered. It is believed that the anion exchange resin exerts the effect of lowering cholesterol level through the mode of action as described above.
Typical of drugs for treating hypercholesterolemia which are known today are as follows. For example, cholestyramine has been widely used in a clinic as a priority drug for treating familial hypercholesterolemia; however, it has a disadvantage that it adsorbs fat-soluble vitamins under the influence of hydrophobic interaction, thereby making it necessary to supply fat-soluble vitamins such as vitamins K and D to make up for the poverty thereof in the case of the prolonged administration of cholestyramine. In addition, conventional cholesterol-lowering drugs including cholestyramine preparations are inconvenient in that they should be suspended before use. Cholestyamine has another disadvantage that a patient is forced to take a large dose (8 to 16 g per day) because of its poor capability of adsorbing bile acids, thus inflicting a burden to the patient. Furthermore, it is known that a cross-linked polymer is expanded in volume through swelling. This is sometimes clinically observed as side effects including abdominal swelling and constipation. Furthermore, a still another disadvantage is that some patients will not take the drug as directed by the doctor because of said problems raised at the time of administration of the above conventional drugs.
As an existing technique for solving the above-mentioned problems, Sugii et al. of Kumamoto University introduced an .omega.-oxobutyl chain as a spacer between an aliphatic quaternary ammonium salt and a main polystyrene chain and thus improved the accessibility of bile acids to an ion exchange group and the hydrophobic interaction of the spacer to thereby enhance the adsorption affinity, thus increasing the amount of bile acids discharged in feces [see J. Pharmacobio-Dyn., 13, 130-135 (1990)]. However, this ion exchange resin has a still low bile acid adsorptivity and therefore it exerts only an insufficient effect of lowering a blood cholesterol level.
On the other hand, existing water-soluble quaternarized polymers such as cationized cellulose will highly irritate the mucosae when used and thus they do not satisfy the practical usefulness as a drug for internal use.
It is an object of the present invention to provide a cholesterol-lowering drug which can be easily taken in the form of, for example, tablets, granules and capsules, which relieves side effects such as abdominal swelling and constipation experienced in the conventional cholesterol-lowering drugs containing cross-linked ion exchange resins, which overcomes their disadvantages of adsorbing fat-soluble vitamins and forcing a patient to have a large burden at the time of their administration and which eliminates the inconvenience that they must be suspended before use.